Chronic central versus systemic blockade of AT1 receptors and cardiac dysfunction in rats post-myocardial infarction
Chronic central versus systemic blockade of AT1 receptors and cardiac dysfunction in rats post-myocardial infarction
复制标题
DOI：
10.1152/ajpheart.00317.2009
复制
发表时间：
2009-09-01
影响因子：
4.8
通讯作者：
Leenen, Frans H. H.
中科院分区：
文献类型：
--
作者：
Huang, Bing S.;Ahmad, Monir;Leenen, Frans H. H.
Huang BS，Ahmad M，Tan J，Leenen FH.心肌梗死后大鼠AT（1）受体慢性中枢与全身阻滞与心功能不全Am J Physiol Heart Circ Physiol 297：H968-H975，2009.首次发表于2009年7月17日; doi：10.1152/ajpheart.00317.2009。在大鼠中，中枢和全身ANG II 1型（AT（1））受体阻滞剂均能减弱交感神经功能亢进，但中枢阻滞剂更有效地减轻心肌梗死（MI）后左心室（LV）功能障碍。在方案I中，我们研究了是否对心脏负荷的功能性影响可能发挥作用，以及不同的心脏效应在解除阻滞后消失。Wistar大鼠MI后4周，脑室内输注（1 mg.kg（-1）.day（-1））或皮下注射（100 mg. kg（-1）.day（-1））氯沙坦。在MI后4周和6周评估LV尺寸和功能，即，停药后2 wk。MI后4周和6周，左室内径增大，射血分数降低.侧脑室注射而非皮下注射氯沙坦可显著改善这些参数。6周时，左室收缩压峰值（LVPSP）和压力随时间变化的最大或最小一阶导数（dP/dt（max/min））降低，左室舒张末期压（LVEDP）升高。所有四项指标均由先前的脑室注射氯沙坦改善，而皮下注射氯沙坦仅改善LVEDP。在方案II中，我们评估了MI后4周口服而不是皮下注射氯沙坦的效果。洛沙坦（类似于200 mg.kg（-1）.day（-1））通过饮水或灌胃同样降低脑核中AT（1）受体结合密度，改善LVEDP，但进一步降低LVPSP和dP/dt（max）。这些结果表明，外周AT（1）受体阻滞剂对心脏负荷的影响或皮下给药与口服给药的药代动力学特征，并不导致MI后中枢与全身AT（1）受体阻滞剂对心脏的不同影响。
Huang BS, Ahmad M, Tan J, Leenen FH. Chronic central versus systemic blockade of AT(1) receptors and cardiac dysfunction in rats post myocardial infarction. Am J Physiol Heart Circ Physiol 297: H968-H975, 2009. First published July 17, 2009; doi: 10.1152/ajpheart.00317.2009.-In rats, both central and systemic ANG II type 1 (AT(1)) receptor blockade attenuate sympathetic hyperactivity, but central blockade more effectively attenuates left ventricular (LV) dysfunction post-myocardial infarction (MI). In protocol I, we examined whether functional effects on cardiac load may play a role and different cardiac effects disappear after withdrawal of the blockade. Wistar rats were infused for 4 wk post-MI intracerebroventricularly (1 mg.kg(-1).day(-1)) or injected subcutaneously daily (100 mg.kg(-1).day(-1)) with losartan. LV dimensions and function were assessed at 4 wk and at 6 wk post- MI, i.e., 2 wk after discontinuing treatments. At 4 and 6 wk post- MI, LV dimensions were increased and ejection fraction was decreased. Intracerebroventricular but not subcutaneous losartan significantly improved these parameters. At 6 wk, LV peak systolic pressure (LVPSP) and maximal or minimal first derivative of change in pressure over time (dP/dt(max/min)) were decreased and LV end-diastolic pressure (LVEDP) was increased. All four indexes were improved by previous intracerebroventricular losartan, whereas subcutaneous losartan improved LVEDP only. In protocol II, we evaluated effects of oral instead of subcutaneous administration of losartan for 4 wk post-MI. Losartan (similar to 200 mg.kg(-1).day(-1)) either via drinking water or by gavage similarly decreased AT(1) receptor binding densities in brain nuclei and improved LVEDP but further decreased LVPSP and dP/dt(max). These results indicate that effects on cardiac load by peripheral AT(1) receptor blockade or the pharmacokinetic profile of subcutaneous versus oral dosing do not contribute to the different cardiac effects of central versus systemic AT(1) receptor blockade post-MI.